ABSTRACT
Natural prokaryotic gene repression systems often exploit DNA looping to increase the local concentration of gene repressor proteins at a regulated promoter via contributions from repressor proteins bound at distant sites. Using principles from the Escherichia coli lac operon we design analogous repression systems based on target sequence-programmable Transcription Activator-Like Effector dimer (TALED) proteins. Such engineered switches may be valuable for synthetic biology and therapeutic applications. Previous TALEDs with inducible non-covalent dimerization showed detectable, but limited, DNA loop-based repression due to the repressor protein dimerization equilibrium. Here, we show robust DNA loop-dependent bacterial promoter repression by covalent TALEDs and verify that DNA looping dramatically enhances promoter repression in E. coli. We characterize repression using a thermodynamic model that quantitates this favorable contribution of DNA looping. This analysis unequivocally and quantitatively demonstrates that optimized TALED proteins can drive loop-dependent promoter repression in E. coli comparable to the natural LacI repressor system. This work elucidates key design principles that set the stage for wide application of TALED-dependent DNA loop-based repression of target genes.
ABSTRACT
Polygenic scores (PGS) have transformed human genetic research and have multiple potential clinical applications, including risk stratification for disease prevention and prediction of treatment response. Here, we present a series of recent enhancements to the PGS Catalog (www.PGSCatalog.org), the largest findable, accessible, interoperable, and reusable (FAIR) repository of PGS. These include expansions in data content and ancestral diversity as well as the addition of new features. We further present the PGS Catalog Calculator (pgsc_calc, https://github.com/PGScatalog/pgsc_calc), an open-source, scalable and portable pipeline to reproducibly calculate PGS that securely democratizes equitable PGS applications by implementing genetic ancestry estimation and score normalization using reference data. With the PGS Catalog & calculator users can now quantify an individual's genetic predisposition for hundreds of common diseases and clinically relevant traits. Taken together, these updates and tools facilitate the next generation of PGS, thus lowering barriers to the clinical studies necessary to identify where PGS may be integrated into clinical practice.
ABSTRACT
OBJECTIVE: Effective health communication is critical for understanding and acting on health information. This cross-sectional study explored participants' understanding of their health condition, their preferences for receiving health communications, and their interest in receiving clinical trial results across several therapeutic areas. METHODS: The study recruited participants via social media, email newsletters, and advocacy organizations. An online screener captured demographic information (health conditions, age, race/ethnicity, gender, and education). Eligible participants were emailed an online survey assessing preferred sources and formats for receiving health information, interest in learning about topics related to the results of clinical trials, and health literacy levels. RESULTS: In total, 449 participants (median age, 35 years [range, 18-76]; White, 53%; higher education, 65%; mean (range) health literacy score, 1.9 [0.4-3.0]) from 45 US states completed the survey representing 12 disease indications (bipolar, blood and solid tumor cancers, irritable bowel syndrome, inflammatory bowel disease, major depressive disorder, migraine, Parkinson's, psoriasis/atopic dermatitis, retinal vein occlusion/macular degeneration, rheumatoid arthritis, and spasticity). Healthcare providers were the preferred source of health information (59%), followed by Internet searches (11%). Least preferred sources were social media (5%), friends/family (3%), and email newsletters (2%). Participants preferred multiple formats and ranked reading materials online as most preferred (33%), along with videos (28%) and infographics (27%). Printed materials (14%) and audio podcasts (9%) were the least preferred formats. A majority of the participants reported that the health information they found was hard to understand (57%) and confusing (62%). Most participants (85%) were somewhat/very interested in learning about clinical trial results, with the highest interest in short summaries of safety (78%) and efficacy (74%) results. CONCLUSION: Effective health communication may be achieved via multiple formats shared directly by healthcare providers.
Researchers wanted to learn how people preferred to receive health-related communications, including information about the results of clinical trials. They surveyed 449 people from 45 US states with 12 different health conditions. The survey questions asked people about their preferred sources and ways of getting health information. It also asked about their interest in learning about clinical trials related to their health condition. The results showed that most people preferred to get health information from their healthcare providers (59%). The Internet was the second most popular choice (11%) for getting health information. People did not like getting health information from social media, friends or family, or email newsletters as much. When it came to how health information was shared, people liked reading materials online (33%), watching videos (28%), and looking at infographics (27%). They did not like printed materials and audio podcasts as much. Most people (85%) were interested in learning about the results of clinical trials in short summaries. They wanted to know about the safety (78%) and how well the treatments worked (74%) in the short summaries. In conclusion, people liked getting health information from healthcare providers like doctors, nurses, and others in different formats. Sharing information in different formats through healthcare providers may improve communication for patients with different health conditions.
ABSTRACT
BACKGROUND: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make realtime treatment decisions for children with relapsed/refractory solid tumors. METHODS: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make realtime treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. RESULTS: A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy. CONCLUSIONS: This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.
Subject(s)
Neuroblastoma , Child , Humans , Neuroblastoma/drug therapy , Neuroblastoma/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/etiologyABSTRACT
BACKGROUND: Missouri has one of the highest rates of maternal mortality in the United States. To date, there are currently no studies describing birthing peoples' knowledge or perceptions of contributing causes of maternal mortality. An improved understanding of population-specific knowledge can help to define how best to design targeted interventions to reduce disease-specific causes of maternal mortality. OBJECTIVE: This study aimed to examine the knowledge and understanding of maternal mortality in a Missouri birthing population. STUDY DESIGN: A 46-question, cross-sectional survey to assess the familiarity with local maternal mortality rates, groups affected, and causality was developed by the Missouri Perinatal Quality Collaborative and the Maternal-Child Learning and Action Network and emailed to a random sample of birthing people across Missouri. Those who identified as someone with birthing potential with a Missouri zip code and who were ≥18 years of age were eligible for inclusion. Unadjusted descriptive statistics were generated and stratified by age, race, and region. RESULTS: Among 2196 surveys sent, 1738 people completed the survey. Of those who responded, 78.2% were aware of the risk of pregnancy-related death with 14.7% reporting that they intimately knew someone who died. When asked if a certain group is affected disproportionately more, 66.4% responded affirmatively. Black (58.7%), uninsured (61.8%), poor (71.0%), those with substance abuse disorders (57.4%), and Native American (28.8%) birthing people were identified as groups that were perceived as suffering higher rates of maternal death. When polled on etiology, severe bleeding (56.9%) was believed to be the leading cause of death, and the second stage of labor was thought to be the period of highest risk (42.3%). Beliefs about the timing of death differed by age (P=.042) but not race (P=.81) or region (P=.191). CONCLUSION: Missouri birthing people are cognizant of the social factors associated with increased maternal mortality but are unaware of the leading causes of death, namely cardiovascular disease and mental health conditions. Future Perinatal Quality Collaborative work should focus on campaigns that raise public awareness about cardiovascular disease and mental health-related birthing risks and the importance of monitoring early warning signs after delivery.
Subject(s)
Cardiovascular Diseases , Health Knowledge, Attitudes, Practice , Maternal Mortality , Humans , Female , Adult , Maternal Mortality/trends , Cross-Sectional Studies , Pregnancy , Missouri/epidemiology , Cardiovascular Diseases/mortality , Cardiovascular Diseases/psychology , Cardiovascular Diseases/epidemiology , Young Adult , Adolescent , Middle Aged , Surveys and Questionnaires , MaleABSTRACT
Immune checkpoint inhibitors (ICIs) are a relatively new class of immunotherapy which bolsters the host immune system by "turning off the brakes" of effector cells (e.g., CTLA-4, PD-1, PD-L1). Although their success in treating adult malignancy is well documented, their utility in pediatric cancer has not yet been shown to be as fruitful. We review ICIs, their use in pediatric malignancies, and active pediatric clinical trials, exemplifying some of adult efforts that could be related to pediatric future trials and complications of ICI therapy. Through our review, we propose the consideration of ICI as standard therapy in lymphoma and various solid tumor types, especially in relapsed or refractory (R/R) disease. However, further studies are needed to demonstrate ICI effectiveness in pediatric leukemia.
ABSTRACT
Importance: People experiencing homelessness (PEH) face disproportionately high mortality rates compared with the general population, but few studies have examined mortality in this population by age, gender, and race and ethnicity. Objective: To evaluate all-cause and cause-specific mortality in a large cohort of PEH by age, gender, and race and ethnicity. Design, Setting, and Participants: An observational cohort study was conducted from January 1, 2003, to December 31, 2018. All analyses were performed between March 16, 2021, and May 12, 2022. A cohort of adults (age ≥18 years) seen at the Boston Health Care for the Homeless Program (BHCHP), a large federally funded Health Care for the Homeless organization in Boston, Massachusetts, from January 1, 2003, to December 31, 2017, was linked to Massachusetts death occurrence files spanning January 1, 2003, to December 31, 2018. Main Outcomes and Measures: Age-, gender-, and race and ethnicity-stratified all-cause and cause-specific mortality rates were examined and compared with rates in the urban Northeast US population using mortality rate ratios (RRs). Results: Among the 60â¯092 adults included in the cohort with a median follow-up of 8.6 (IQR, 5.1-12.5) years, 7130 deaths occurred. The mean (SD) age at death was 53.7 (13.1) years; 77.5% of decedents were men, 21.0% Black, 10.0% Hispanic/Latinx, and 61.5% White. The all-cause mortality rate was 1639.7 deaths per 100â¯000 person-years among men and 830 deaths per 100â¯000 person-years among women. The all-cause mortality rate was highest among White men aged 65 to 79 years (4245.4 deaths per 100â¯000 person-years). Drug overdose was a leading cause of death across age, gender, and race and ethnicity groups, while suicide uniquely affected young PEH and HIV infection and homicide uniquely affected Black and Hispanic/Latinx PEH. Conclusions and Relevance: In this large cohort study of PEH, all-cause and cause-specific mortality varied by age, gender, and race and ethnicity. Tailored interventions focusing on those at elevated risk for certain causes of death are essential for reducing mortality disparities across homeless-experienced groups.
Subject(s)
HIV Infections , Ill-Housed Persons , Adult , Male , Humans , Female , Ethnicity , Cohort Studies , Massachusetts/epidemiologyABSTRACT
Precipitation indices based on daily gauge observations are well established, openly available and widely used to detect and understand climate change. However, in many areas of climate science and risk management, it has become increasingly important to understand precipitation characteristics, variability and extremes at shorter (sub-daily) durations. Yet, no unified dataset of sub-daily indices has previously been available, due in large part to the lesser availability of suitable observations. Following extensive efforts in data collection and quality control, this study presents a new global dataset of sub-daily precipitation indices calculated from a unique database of 18,591 gauge time series. Developed together with prospective users, the indices describe sub-daily precipitation variability and extremes in terms of intensity, duration and frequency properties. The indices are published for each gauge where possible, alongside a gridded data product based on all gauges. The dataset will be useful in many fields concerned with variability and extremes in the climate system, as well as in climate model evaluation and management of floods and other risks.
ABSTRACT
Children with relapsed/refractory (R/R) neuroblastoma (NB) and medulloblastoma (MB) have poor outcomes. We evaluated the efficacy of nifurtimox (Nfx) in a clinical trial for children with R/R NB and MB. Subjects were divided into three strata: first relapse NB, multiply R/R NB, and R/R MB. All patients received Nfx (30 mg/kg/day divided TID daily), Topotecan (0.75 mg/m2 /dose, days 1-5) and Cyclophosphamide (250 mg/m2 /dose, days 1-5) every 3 weeks. Response was assessed after every two courses using International Neuroblastoma Response Criteria and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. One hundred and twelve eligible patients were enrolled with 110 evaluable for safety and 76 evaluable for response. In stratum 1, there was a 53.9% response rate (CR + PR), and a 69.3% total benefit rate (CR + PR + SD), with an average time on therapy of 165.2 days. In stratum 2, there was a 16.3% response rate, and a 72.1% total benefit rate, and an average time on study of 158.4 days. In stratum 3, there was a 20% response rate and a 65% total benefit rate, an average time on therapy of 105.0 days. The most common side effects included bone marrow suppression and reversible neurologic complications. The combination of Nfx, topotecan and cyclophosphamide was tolerated, and the objective response rate plus SD of 69.8% in these heavily pretreated populations suggests that this combination is an effective option for patients with R/R NB and MB. Although few objective responses were observed, the high percentage of stabilization of disease and prolonged response rate in patients with multiply relapsed disease shows this combination therapy warrants further testing.
Subject(s)
Cerebellar Neoplasms , Medulloblastoma , Neuroblastoma , Child , Humans , Topotecan/adverse effects , Nifurtimox/therapeutic use , Medulloblastoma/drug therapy , Neoplasm Recurrence, Local/pathology , Neuroblastoma/drug therapy , Neuroblastoma/etiology , Cyclophosphamide , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Background: Mobile health clinics improve access to care for marginalized individuals who are disengaged from the healthcare system. This study evaluated the association between a mobile addiction health clinic and health care utilization among people experiencing homelessness. Methods: Using Medicaid claims data, we evaluated adults who were seen by a mobile addiction health clinic in Boston, Massachusetts from 1/16/18-1/15/19 relative to a propensity score matched control cohort. We evaluated both cohorts from four years before to one year after the index visit date with the mobile clinic. The primary outcome was the number of outpatient visits; secondary outcomes were the number of hospitalizations and emergency department (ED) visits. We used Poisson regression to compare changes in outcomes from before to after the index date in a quasi-experimental design. Results: 138 adults were seen by the mobile clinic during the observation period; 29.7% were female, 16.7% were Black, 8.0% Hispanic, 68.1% White, and the mean age was 40.4 years. The mean number of mobile clinic encounters was 3.1. The yearly mean number of outpatient visits increased from 11.5 to 12.1 (p = 0.43; pdiff-in-diff = 0.15), the number of hospitalizations increased from 2.2 to 3.0 (p = 0.04; pdiff-in-diff = 0.87), and the number of ED visits increased from 5.4 to 6.5 (p = 0.04; pdiff-in-diff = 0.40). Conclusions: The mobile addiction health clinic was not associated with statistically significant changes in health care utilization in the first year. Further research in larger samples using a broader set of outcomes is needed to quantify the benefits of this innovative care delivery model.
Subject(s)
Ill-Housed Persons , Telemedicine , United States , Adult , Humans , Female , Male , Boston/epidemiology , Mobile Health Units , Delivery of Health Care , Patient Acceptance of Health Care , Massachusetts , Emergency Service, Hospital , Retrospective StudiesABSTRACT
This cohort study involves assessing causes of death among people experiencing homelessness in Boston from 2003 to 2018.
Subject(s)
Ill-Housed Persons , Adult , Humans , Boston , MassachusettsABSTRACT
BACKGROUND: The senior leadership course at the University of Pennsylvania School of Nursing includes both didactic and clinical components. The didactic portion delves into leadership topics and during clinical rotations the students witness nurses and patients navigate through complicated and emotional patient care experiences. METHOD: Structured, active, in-class learning (SAIL) activities in a classroom were used to connect didactic content with clinical scenarios. Different specialty-related clinical scenarios were presented to the students, and they were allocated a certain amount of time for discussion in small groups before sharing their outcomes with the whole group (think-pair-share). RESULTS: Student evaluations showed that the percentage of students who rated each session as excellent increased each semester and feedback remained overwhelmingly positive; the consistently identified area for improvement is the timing and we plan to lengthen the sessions to address that. CONCLUSION: Our team discovered that by shifting most of our simulation scenarios to SAIL, we provided the students with ample opportunities to speak in a dialectically rich environment about clinical scenarios while maintaining the interrelation between theory and practice. [J Nurs Educ. 2023;62(4):257-262.].
Subject(s)
Education, Nursing, Baccalaureate , Simulation Training , Students, Nursing , Humans , Leadership , Problem-Based Learning , Students, Nursing/psychologyABSTRACT
The NHGRI-EBI GWAS Catalog (www.ebi.ac.uk/gwas) is a FAIR knowledgebase providing detailed, structured, standardised and interoperable genome-wide association study (GWAS) data to >200 000 users per year from academic research, healthcare and industry. The Catalog contains variant-trait associations and supporting metadata for >45 000 published GWAS across >5000 human traits, and >40 000 full P-value summary statistics datasets. Content is curated from publications or acquired via author submission of prepublication summary statistics through a new submission portal and validation tool. GWAS data volume has vastly increased in recent years. We have updated our software to meet this scaling challenge and to enable rapid release of submitted summary statistics. The scope of the repository has expanded to include additional data types of high interest to the community, including sequencing-based GWAS, gene-based analyses and copy number variation analyses. Community outreach has increased the number of shared datasets from under-represented traits, e.g. cancer, and we continue to contribute to awareness of the lack of population diversity in GWAS. Interoperability of the Catalog has been enhanced through links to other resources including the Polygenic Score Catalog and the International Mouse Phenotyping Consortium, refinements to GWAS trait annotation, and the development of a standard format for GWAS data.
Subject(s)
Genome-Wide Association Study , Knowledge Bases , Animals , Humans , Mice , DNA Copy Number Variations , National Human Genome Research Institute (U.S.) , Phenotype , Polymorphism, Single Nucleotide , Software , United StatesABSTRACT
OBJECTIVES: To assess the 6-month incidence of laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, postnatal care, hospitalization, and mortality among infants born to people with laboratory-confirmed SARS-CoV-2 infection during pregnancy by timing of maternal infection. METHODS: Using a cohort of liveborn infants from pregnancies with SARS-CoV-2 infections in the year 2020 from 10 United States jurisdictions in the Surveillance for Emerging Threats to Mother and Babies Network, we describe weighted estimates of infant outcomes from birth through 6 months of age from electronic health and laboratory records. RESULTS: Of 6601 exposed infants with laboratory information through 6 months of age, 1.0% (95% confidence interval: 0.8-1.1) tested positive, 19.1% (17.5-20.6) tested negative, and 80.0% (78.4-81.6) were not known to be tested for SARS-CoV-2. Among those ≤14 days of age, SARS-CoV-2 infection occurred only with maternal infection ≤14 days before delivery. Of 3967 infants with medical record abstraction, breastmilk feeding initiation was lower when maternal infection occurred ≤14 days before delivery compared with >14 days (77.6% [72.5-82.6] versus 88.3% [84.7-92.0]). Six-month all-cause hospitalization was 4.1% (2.0-6.2). All-cause mortality was higher among infants born to people with infection ≤14 days (1.0% [0.4-1.6]) than >14 days (0.3% [0.1-0.5]) before delivery. CONCLUSIONS: Results are reassuring, with low incidences of most health outcomes examined. Incidence of infant SARS-CoV-2, breastmilk feeding initiation, and all-cause mortality differed by timing of maternal infection. Strategies to prevent infections and support pregnant people with coronavirus disease 2019 may improve infant outcomes.
Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Pregnancy , Female , Humans , United States/epidemiology , Infant , Infant, Newborn , SARS-CoV-2 , COVID-19/epidemiology , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/epidemiology , Pregnancy Complications, Infectious/prevention & control , Pregnancy Outcome/epidemiology , COVID-19 Testing , Infectious Disease Transmission, Vertical/prevention & controlABSTRACT
Objectives. To describe prevalence of breast milk feeding among people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and examine associations between breast milk feeding, timing of maternal infection before delivery, and rooming-in status during delivery hospitalization. Methods. We performed a retrospective cohort study using data from Massachusetts, Minnesota, Nebraska, Pennsylvania, and Tennessee of whether people with confirmed SARS-CoV-2 infection during pregnancy in 2020 initiated breast milk feeding at birth. Results. Among 11 114 (weighted number) people with SARS-CoV-2 infection in pregnancy, 86.5% (95% confidence interval [CI] = 82.4%, 87.6%) initiated breast milk feeding during birth hospitalization. People with infection within 14 days before delivery had significantly lower prevalence of breast milk feeding (adjusted prevalence ratio [APR] = 0.88; 95% CI = 0.83, 0.94) than did those with infection at least 14 days before delivery. When stratified by rooming-in status, the association between timing of infection and breast milk feeding remained only among infants who did not room in with their mother (APR = 0.77; 95% CI = 0.68, 0.88). Conclusions. Pregnant and postpartum people with SARS-CoV-2 infection should have access to lactation support and be advised about the importance of breast milk feeding and how to safely feed their infants in the same room. (Am J Public Health. 2022;112(S8):S787-S796. https://doi.org/10.2105/AJPH.2022.307023).
Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Pregnancy , Infant, Newborn , Female , Humans , COVID-19/epidemiology , Milk, Human , SARS-CoV-2 , Retrospective Studies , Breast Feeding , Pregnancy Complications, Infectious/epidemiologyABSTRACT
Short-duration precipitation extremes (PE) increase at a rate of around 7%/K explained by the Clausius-Clapeyron relationship. Previous studies show uncertainty in the extreme precipitation-temperature relationship (scaling) due to various thermodynamic/dynamic factors. Here, we show that uncertainty may arise from the choice of data and methods. Using hourly precipitation (PPT) and daily dewpoint temperature (DPT) across 2,905 locations over the United States, we found higher scaling for quality-controlled data, all locations showing positive (median 6.2%/K) scaling, as compared to raw data showing positive (median 5.3%/K) scaling over 97.5% of locations. We found higher scaling for higher measurement precision of PPT (0.25 mm: median 7.8%/K; 2.54 mm: median 6.6%/K). The method that removes seasonality in PPT and DPT gives higher (with seasonality: median 6.2%/K; without seasonality: median 7.2%/K) scaling. Our results demonstrate the importance of quality-controlled, high-precision observations and robust methods in estimating accurate scaling for a better understanding of PE change with warming.
ABSTRACT
Introduction: The COVID-19 pandemic caused a pause to nearly all sporting activities in the spring of 2020, and collegiate athletes at the National Collegiate Athletic Association (NCAA)-affiliated universities whose sporting seasons were affected by the pandemic were granted an extra year of athletic eligibility. This study was conducted to determine how collegiate athletes planned to use an additional year of eligibility granted by the NCAA. Methods: The authors conducted a cross-sectional survey of 632 athletes from two universities in the Midwestern United States, between August and September 2021. The athletes completed an anonymous, nine-item survey to assess the effect of the pandemic on the athletic season, athletic eligibility, and potential change in an academic or professional career. Chi-square tests, generalized linear mixed models, and adjusted odds ratio were used for the analyses. Results: The participation rate was 74.5% (471 of 632). Nearly 63% (290 of 461) of the athletes received an additional year of eligibility because of the pandemic, with 193 (66.6%) planned to use their extra year for scholastic development. Male athletes (65.3% vs. 34.7%; χ2[1, n = 290] = 11.66, p < 0.001, Φ = 0.20), Division II athletes (59.6% vs. 40.4%; χ2[1, n = 290] = 13.93, p < 0.001, Φ = 0.22), and athletes who had not previously used redshirt (73.1% vs. 26.9%; χ2[1, n = 290] = 4.79, p = 0.029, Φ = 0.32) where more likely to use their extra year of eligibility academically. Conclusions: Our findings suggested that most of the athletes planned to use their extra year of eligibility to pursue further scholastic or professional development, highlighting the positive part of the COVID-19 pandemic. Future studies should investigate how these findings relate to athletes from universities in different geographical locations and intra-division schools.
ABSTRACT
BACKGROUND: Survival for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies. AIMS: To study the feasibility and safety of incorporating a genomic-based targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti-GD2 immunotherapy. METHODS: Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial. Molecular tumor boards selected one of six targeted agents based on tumor-normal whole exome sequencing and tumor RNA-sequencing results. Treatment followed standard upfront HRNB chemotherapy with the addition of the selected targeted agent to cycles 3-6 of induction. Following consolidation, DFMO (750 mg/m2 twice daily) was added to maintenance with dinutuximab and isotretinoin, followed by continuation of DFMO alone for 2 years. DNA methylation analysis was performed retrospectively and compared to RNA expression. RESULTS: Of the 20 subjects enrolled, 19 started targeted therapy during cycle 3 and 1 started during cycle 5. Eighty-five percent of subjects met feasibility criteria (receiving 75% of targeted agent doses). Addition of targeted agents did not result in toxicities requiring dose reduction of chemotherapy or permanent discontinuation of targeted agent. Following standard consolidation, 15 subjects continued onto immunotherapy with DFMO. This combination was well-tolerated and resulted in no unexpected adverse events related to DFMO. CONCLUSION: This study demonstrates the safety and feasibility of adding targeted agents to standard induction therapy and adding DFMO to immunotherapy for HRNB. This treatment regimen has been expanded to a Phase II trial to evaluate efficacy.
Subject(s)
Antineoplastic Agents , Neuroblastoma , Humans , Eflornithine/adverse effects , Pilot Projects , Induction Chemotherapy , Retrospective Studies , Neuroblastoma/drug therapy , Neuroblastoma/genetics , Immunotherapy , Antineoplastic Agents/therapeutic use , Immunologic Factors , Genomics , RNA/therapeutic useABSTRACT
Microbial proteins are potentially important alternatives to animal protein. A safety assessment was conducted on a Clostridium protein which can serve as a high-quality protein source in human food. A battery of toxicity studies was conducted comprising a 14-day dose-range finding dietary study in rats, 90-day dietary study in rats and in vitro genotoxicity studies. The allergenic potential was investigated by bioinformatics analysis. In the 90-day feeding study, rats were fed diets containing 0, 5.0, 7.5, and 10% Clostridium protein. The Clostridium protein-containing diets were well-tolerated and no adverse effects on the health or growth were observed. Significant reductions in neutrophil counts were observed in all female rats compared to controls, which were slightly outside of reference ranges. These effects were not deemed to be adverse due to the absence of comparable findings in male rats and high physiological variability of measured values within groups. A No-Observed-Adverse-Effect-Level (NOAEL) of at least 10% Clostridium protein, the highest dose tested and corresponding to 5,558 and 6,671 mg/kg body weight/day for male and female rats, respectively, was established. No evidence of genotoxicity was observed and the allergenic potential was low. These results support the use of Clostridium protein as a food ingredient.